Up to the early 1990s, there was little schizophrenia research being undertaken in NSW. The few investigators involved were poorly resourced, and had minimal access to research infrastructure. All this started to change in 1991 when Dr Stanley Catts led a group of scientists, clinicians and concerned parent-carers to propose the formation of an institute dedicated to developing world-class standards of schizophrenia research in NSW. With the backing of key groups such as the Schizophrenia Fellowship of NSW, the NSW Labor Council and the Construction Forestry Mining Energy Union, SRI presented a strong case for State Government support, which was ultimately awarded by the NSW Labor Party upon winning office in 1995.

Critically, these early years of development also forged firm partnerships between the consumers/carers and the research community, and vital accord between neuroscientists and clinicians regarding the structure of the Institute. An innovative “institute without walls” structure was adopted to provide infrastructure and support, and to enhance networking and collaboration between existing NSW centres. The plan was to avoid the expense of a separate ‘bricks and mortar’ institute and to utilise the human and technical resources of existing NSW facilities.

The first years of operations were focussed on establishing the necessary infrastructure. The Schizophrenia Research Register: a database of patients and family members willing to participate in research; the NSW Tissue Resource Centre: a ‘bank’ of postmortem brains; the ‘Gift of Hope’ Brain Donor Program: allowing people to authorise post-mortem donations; the Hunter DNA Bank: a database of the DNA profiles of schizophrenia patients, their families and others, and the Virtual Brain Bank: a library of MRI brain scans from people with schizophrenia at various stages of their illness. These NSW research facilities have since been so successful in supporting world-class research that SRI was successful in attracting NHMRC and Pratt Foundation funding in 2006 to expand elements of them into a national facility called the Australian Schizophrenia Research Bank (ASRB) – in collaboration with researchers from Queensland, Western Australia and Victoria.

As such infrastructures came ‘online’, SRI was able to initiate and/or support increasing numbers of research studies, as well as to engage in national and international collaborations. Under the successive Scientific Directorships of Professors Stan Catts, Philip Ward and Vaughan Carr, the Institute and its affiliated scientists have been awarded over $15 million in external grant funding, supporting original research producing 140 published scientific papers and 400 presentations at national and international scientific conferences.

The ‘hands on’ laboratory work that produces such papers is often carried out by research higher degree students (e.g. Honours, Masters, PhD) studying to become the senior scientists of the future. To nurture such researchers, and to attract the best minds into schizophrenia research, SRI has to date provided support to around 75 students, 35 of whom have already achieved their degrees.

What are the most significant discoveries SRI has made in its first decade?

Despite the time and resources expended on creating essential infrastructure, SRI and affiliated scientists have played a vital role in many recent findings of Australian schizophrenia research. A few highlights of these include:

Using a new fMRI brain scanning technique to demonstrate, for the first time, a correlation between areas of reduced regional cortical thickness and impaired brain function in first-episode schizophrenia;

Identifying differences in the brain’s auditory processing (known as mismatch negativity), which has been proposed as a biological marker of vulnerability to schizophrenia;

Using a new computer-based remediation tool to demonstrate improved recognition of facial expressions of emotion in schizophrenia, with increased visual attention to important facial features, suggesting the utility of computer training tools in remediation of facial emotion recognition impairments;

Discovery that blood lymphocytes can be used to identify distinct gene expression profiles within schizophrenia, which may be useful in the development of a biological basis for diagnosis and subtype classification for the disorder;

Discovery of similar patterns of reduced brain activation in first episode schizophrenia patients and chronic cannabis users during performance of a planning task, suggesting
the possibility of a shared pathology in these conditions;

Demonstrating similar, but attenuated, restricted visual scanpaths in response to facial emotions in first degree biological relatives of schizophrenia patients, providing evidence that visual scanpath dysfunction may be a trait marker in familial transmission of schizophrenia.

In addition to cutting-edge research results, SRI has established Australia’s first University Chair of Schizophrenia Research – in partnership with the University of New South Wales and the Prince of Wales Medical Research Institute. On the public awareness front, SRI has designed and produced Australia’s first schizophrenia early intervention poster – which was distributed nationwide with the assistance of the Mental Illness Fellowship of Australia.

There is genuine optimism within the world-wide research community that we now have the techniques and knowledge to achieve significant breakthroughs in regards to the treatment and prevention of this devastating disease. Ten years on, all SRI contributors and supporters can feel proud of the achievements made to date. The institute has played a major role in creating a vibrant, multidisciplinary network of over 120 Australian clinicians and neuroscientists who are actively collaborating on a range of schizophrenia research initiatives. With an increasing national collaborative research focus, together with the commencement of the Chair of Schizophrenia Research, SRI remains committed to its vision of finding the means to prevent and cure schizophrenia.

Draganic D, Catts S, Carr V. The Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD): 10 years of Australia’s first ‘virtual research institute’. Australian and New Zealand Journal of Psychiatry (in press).

While the Wollongong team’s research is pointing to a promising potential new source of schizophrenia medications, other SRI researchers at the Garvan Institute and the University of Sydney have completed a series of studies into the side effects of current front line medications. Extrapyramidal symptoms (EPS) such as involuntary movements and tremors are often a neurological side effect of antipsychotic medication. Many people who take ‘typical’ antipsychotics experience some form of EPS, and it has been estimated that more than 70 per cent of patients discontinue treatment because of these side effects. While new ‘atypical’ antipsychotics appear to carry less risk of EPS, they have been associated with obesity and diabetes.

SRI researchers at the Garvan Institute and the University of Sydney devised a three-stage collaborative project, using laboratory animals to investigate the causes of EPS and other side effects. In the first stage of the study (1) at the Garvan Institute, rats were divided into four groups. The first group received no treatment; the second received a neutral solution; the third received regular doses of a ‘typical’ antipsychotic, and the fourth group received regular
doses of an ‘atypical’ antipsychotic.

SRI’s integrated research into the side effects of antipsychotics involved three specialist groups at two research centres.

Over 28 days of treatment, the team observed the behaviour of these animals and found that both groups of drug- treated rats exhibited EPS-like symptoms, diminished activity, impaired working memory, and increased anxiety. These effects were more pronounced in the ‘typical-treated’ animals, suggesting that these differences in the behavioural profile were likely due to the unique receptor activation of the ‘typical’ antipsychotic.

In the second stage of the study (2), the brains from the ‘atypical’-treated rats and those treated with a neutral solution were analysed using proteomic methods by SRI’s team at the University of Sydney. Analysis of proteins in mental health research is considered important because
proteins are the building blocks of the brain, and the types and numbers of them present in individual brains indicate the activity of the specific genes which design them.

The University of Sydney team found that 31 proteins had changed in the brain tissue of the ‘atypical’ rats compared to the neutral group (the ‘typical’ group is currently being tested), and that the types of these proteins indicated that the ‘atypical’ treatment had triggered cellular metabolic dysfunction and oxidative stress, which may be the causes of EPS and other side effects.

The third stage of the study (3) investigated the obesity and diabetes aspect of side effects by recruiting the expertise of the Neuroscience Research Group of the Garvan Institute. This team studied the effects of both antipsychotic-treated rat groups, and found no increase in food intake, body weight or adipose tissue. However, the ‘typical’ group showed increased insulin levels, and the ‘atypical’ group showed increased serum glucagon (glucose) levels – indicating that both antipsychotics had caused a distinct diabetes-related metabolic effect.

This type of integrated research provides us with the best chance of finding the answers to schizophrenia. The study has provided the scientific community with an animal model of antipsychotic drugs in action, which will be valuable to future investigations of side effects and better medications.

SRI’s Beta Imager at Wollongong is helping to cut years off the timeline to new treatments.

While the new ‘atypical’ antipsychotics have proved to be more effective than old style meds, they are still far from perfect. There remains an urgent need to discover additional ways of reducing the symptoms of schizophrenia, and to move towards treatments which restore normal brain function, not just suppress symptoms.

Current antipsychotics modulate the brain’s dopamine activity by blocking the relevant receptors on the surface of brain cells. This blockade causes cells to produce more receptors, thus modulating dopamine neurotransmission. Increasing research evidence suggests that another class of receptor, the muscarinic cholinergic receptor, may be treated in a similar way to upregulate the brain’s acetylcholine activity.

Postmortem brain tissue studies such as those now underway at the University of Wollongong have shown that numbers of specific muscarinic receptors are significantly less than normal in the brains of people with schizophrenia. Moreover, drugs have been synthesised which partially blockade these receptors, with beneficial effects.

The study featured below focussed on the superior temporal gyrus (STG) brain area because it is known to be involved in the pathology of schizophrenia – particularly in auditory hallucinations (hearing voices). The study found that there were up to 48 per cent less muscarinic receptors in the STG of schizophrenia brains than in healthy brains. Increasing evidence suggests that muscarinic-based medications could be of enormous value in the treatment of schizophrenia. In this and other vital research efforts, SRI’s Beta Imager is enabling results that used to take months to be achieved in hours.

A recent example of the research results* achieved by the Beta Imager, the above images show A: a section of post mortem brain tissue with the superior temporal gyrus (STG) area indicated by the white square.
B: the density of M1/4 muscarinic receptors in the STG of a control subject (indicated by yellow/red colouring).
C: M1/4 muscarinic density in the STG of a schizophrenia subject.
D and E: similar differences found in M2/4 muscarinic receptors.

Beta funding for schizophrenia research

The SRI-initiated campaign to raise $200,000 for a Beta Imager was supported by Wollongong City Council and many Illawarra-based companies and the community. Their efforts came to fruition in 2003 with the installation of the only Beta Imager in the Southern Hemisphere at the SRI research centre in the University of Wollongong.

The presence of the machine has had a dramatic impact on Australia’s fight against schizophrenia, and placed the university in the front line of research. The number of schizophrenia researchers has tripled, and funding for the university’s Neurobiology Research Centre for Metabolic and Psychiatric Disorders has risen from $382,000 in the period 1998 – 2001 to $2.1 million during 2002 – 2005.

Prof. Xu-Feng Huang and NISAD PhD Scholar Kelly Newell in the Beta-imaging lab at the University of Wollongong.

“We really want to thank everyone who supported the fund-raising campaign, and let them know that they have made a major contribution in a very difficult area of research – looking at what happens in the human brain,” said Prof. Xu-Feng Huang, the Centre’s Director.

Prof. Huang and his SRI team are researching various neurochemicals in brain tissue – comparing levels found in schizophrenia affected brains with those found in brains unaffected by the illness. The aim is to develop new medications, and to overcome the side effects of current medications – which include the high incidence of obesity among patients.

“The Beta Imager makes our research so much quicker, giving results in a matter of hours where previously we would have had to wait three months,” said Prof. Huang. “This enormous time saving allows us to explore and test our ideas more creatively, knowing that we will very quickly find out whether we are on the right track or not.”

A SRI-supported PhD scholar at the centre, Kelly Newell, said, “We’re getting a lot of results, and people are really taking notice. Recently our group gave 10 presentations to 700 attendees at the Australian Neuroscience Conference in Sydney – our largest number of presentations at a neuroscience conference.”

$1.5 million moves Australian schizophrenia research up to a new national level

Back in 1996 when the Schizophrenia Research Institute began operations, the first task was to establish the infrastructure which would enable research to take place in NSW. It took about 5 years to get a register of research participants, a brain donor program, a DNA bank and a ‘virtual’ brain bank up and running. Supported by these programs, the number of the Institute’s published scientific papers has risen from 5 to 50 per year since 2000.

It was this exponential increase in productivity and the infrastructure foundation in NSW which helped to win SRI an award of $1.75 million from the National Health and Medical Research Council (NHMRC) to develop similar linked infrastructures in other States – creating an Australian Schizophrenia Research Bank (ASRB).

However, the NHMRC funding was sufficient only for the development of NSW, Queensland and WA, meaning that Victoria – the second most populous State in the country – could not be included.

While laying the foundations for the ASRB, SRI successfully approached the Pratt Foundation (one of the largest private sources of philanthropy – established by Richard and Jean Pratt in 1978) ) to provide funding to include Victoria and to support the national structure. The Pratt award of $1.4 million will ensure that the ASRB becomes a truly national resource.

The national quest to find the genes of schizophrenia

With a fund of over $3 million, SRI is now starting its 5-year task of setting up the national network via affiliated mental health centres in Brisbane, Sydney, Newcastle, Orange, Melbourne and Perth. The ASRB will recruit 2,000 people with schizophrenia and 2,000 controls, and obtain brain scans, blood samples and detailed clinical information from these volunteers. The scans will be processed to provide information on brain structure; the blood samples used to produce individual genetic profiles and cell lines, and the clinical information to compile dossiers of personal and family health history. All data will then be cross referenced and linked by a specially developed software grid.

The finished database will be the biggest of its kind in the world and, once made available, be of enormous ongoing value to Australian and international scientists searching for the genetic bases of schizophrenia.

Mobilised by John Singleton AO, one of Australia’s biggest marketing services groups, Singleton Ogilvy & Mather, is creating a national advertising campaign to raise awareness of the Australian Schizophrenia Research Bank, and to attract volunteers from all across the country. The campaign is scheduled to launch in March next year.

“This is a story of the Shannon twins born in September in San Angelo, Texas in the sixties. The boy and girl twin were healthy, happy and well-loved as children, until adolescence hit. As teens, one twin embraced life and socialized and dated; the other twin embraced solitude and withdrew from friends. Both twins started college. One twin made the deans list, the other dropped out. One twin listened to rock music; the other twin heard unpleasant voices. One twin continued college; the other twin entered a mental institution with the subsequent diagnosis of schizophrenia. One twin suffered from adverse reactions to antipsychotic medication, the other twin suffered too. One twin decided something more must be done for people with this horrible disease, and she dedicated her life to this pursuit.”

Ater a national and international search for the best candidate, the Schizophrenia Research Institute is delighted that Dr. Cynthia (Cyndi) Shannon Weickert has accepted the appointment as Australia’s first Chair of Schizophrenia Research. Cyndi graduated with a BA in Biology and Psychology, earned a Ph.D in Biomedical Science, trained in the Neuropathology of Schizophrenia, and became Chief of the MiNDS Unit at the National Institute of Health in Washington DC. She will commence her position as Chair of Schizophrenia Research in December 2006 – a position created by the Institute in partnership with the University of NSW, and the Prince of Wales Medical Research Institute.

Cyndi’s research is focused on determining how normal brain development gets derailed by schizophrenia. She has published several landmark findings which have shifted the attention
of worldwide research onto the role of growth factors and hormones in the development of the illness.

Cyndi brings not only her expertise, but also her passion to Sydney this summer, and she shares in the hope of all Institute supporters for better treatment for all who suffer from schizophrenia, including her twin brother, David.

Why Proteomics is the New Buzzword in Worldwide Schizophrenia Research

The old idea that each of the human body’s 30,000 genes produces a single protein which plays a role in biological construction has been discarded. Current evidence shows that thoughout life, when molecules are required, genes are transcribed first to the corresponding messenger ribonucleic acids (mRNAs), then translated to their protein counterparts – and that this process of transcription and translation is continually subject to modifications arising from genetic predispositions and environmental interactions. Thus it is now estimated that if the human genome contains 30,000 expressed genes, there may be the potential to express as many as one million different proteins – the building blocks of the body and brain.

The prospect of identifying what is now termed an individual’s ‘proteome’ is daunting. Fortunately, the birth of ‘proteomics’, an umbrella term encompassing the many tools available to investigate proteins expressed within cells, fluids, tissues or organisms, has made this task more manageable. These proteomic methods have the power to display and quantify the functional expression of genes, enabling the measurement of disease-associated or phenotypic changes in proteins.

Schizophrenia, with its early developmental and later degenerative/atrophic components, is a particularly complex disorder. We know that multiple, largely unidentified genetic and environmental risk factors interact to lead to disease and disease progression. However, the underlying functional changes at the cellular level remain unknown. This is where the strength of a proteomics approach lies, allowing researchers to identify, quantify and compare the levels of thousands of proteins in different brain areas.

A 2D gel electrophoresis ‘proteome’ showing the levels of expression of proteins in tissue taken from the anterior cingulate cortex (ACC) region of a post mortem human brain. When compared with a gel from a schizophrenia-affected brain, this healthy sample reveals which proteins are expressed differently.

42 protein differences detected in a schizophrenia ‘hot spot’

The brain area known as the anterior cingulate cortex (ACC) plays a fundamental role in cognition and attention, and has been a focus of neuroscience mental health research for some time. Its dysfunction has been directly linked to disorders such as obsessive-compulsive, bipolar and post traumatic stress, as well as to depression, autism and schizophrenia. All evidence identifies the ACC as a mental health ‘hot spot’ in the brain.

An SRI-supported team at the University of Sydney has conducted the world’s first proteomic analysis of the ACC in schizophrenia*, using post mortem tissue from 10 schizophrenia patients and 10 normal controls. The results have identified 42 proteins in the ACC which are differently expressed in schizophrenia, some of which exhibit a 200 percent greater abundance than normal.

The University of Sydney team were able to link all but two of the proteins to specific genes, and has classified them as affecting the synapses, neuronal signaling and other functions. Eight of the altered proteins are involved in energy metabolism within the brain.

Some of the identified proteins have previously been linked to schizophrenia in earlier studies. Others shed new light on the origins of the disease, and present new pieces to fit into the complex puzzle being completed by such research.

The US-based National Alliance for Research on Schizophrenia and Depression (NARSAD) is the largest non-government, donor-supported organization that distributes funds for brain disorder research.

The NARSAD Young Investigator Award Program offers up to US$30,000 a year for up to two years to enable promising investigators to either extend their research fellowship training or to begin careers as independent research faculty.

SRI congratulates Dr Tim Karl and Dr Melissa Green as award winners in 2006. Based at the Garvan Institute, Tim Karl uses animal models to study the effects of genes on brain function and behaviour, and is currently applying this technique to clarify the role of the neuregulin and neuropeptide Y genes in schizophrenia.

At the Macquarie Centre for Cognitive Science Dr Melissa Green is working with Dr Tamara Russell on a training program to remedy abnormal facial emotion perception in people with schizophrenia.

The symptoms of schizophrenia have long been separated into negative and positive types, and individual sufferers usually show a predominance of one type. Some patients, for example, show a diminution or loss of normal functions (negative symptoms), whereas others tend towards an excess or distortion of normal functions expressed in hallucinations and delusions (positive symptoms). Some scientists have proposed that a ‘disorganised’ or ‘cognitive’ type, indicating thought disorder, disorientation, and memory problems, be added as a third category – but this has yet to be generally accepted.

SRI’s Nikola Bowden and a team of Newcastle scientists designed a preliminary investigation to discover if an individual’s schizophrenia type could be identified from a genetic profile obtained from a simple blood sample. 14 patients and 14 matched controls took part in the study (1), which identified 18 brain-related genes significantly altered by schizophrenia (Fig.1). When individual gene profiles were classified by age, distinct gene expression profiles for subgroups of schizophrenia were identified for the first time.

Fig.1: Graph showing the differences in expression of 6,000 genes from 14 schizophrenia participants and 14 healthy controls. Each coloured dot represents a gene, and its colour indicates whether the gene is upregulated (more expressed) or downregulated (less expressed) in schizophrenia subjects compared to controls. Green indicates less expression, yellow equal, and red more expression.

Such gene expression profiling from blood samples may in the future provide a template for individually ‘tailored’ treatments, and larger scale studies on the same lines may lead to a diagnostic tool to assess at-risk status in the early phases of the illness.

Genetic Abnormalities Found in the Amygdala

The amygdala is a part of the brain of special interest to schizophrenia researchers due to the key role it plays in emotion processing. While some studies have reported reduced tissue volumes and neural differences in the amygdala in schizophrenia, the genes involved in its dysfunction have yet to be identified.

Judith Weidenhofer and the SRI affiliated team at the University of Newcastle examined gene expression in the amygdala (2) in postmortem brain tissue of seven matched pairs of schizophrenia and normal control subjects.

Fig.2: The billions of neurons in the brain communicate by sending chemical messages to each other across synapses.

Among other differences, genes involved in presynaptic function (Fig.2) were found to be consistently dysregulated in the schizophrenia samples.

These results are the first evidence that genes involved in presynaptic mechanisms in the amygdala are implicated in the pathophysiology of schizophrenia.

Schizophrenia and Substance Use Breaking the Cycle of Cigarette and Cannabis Smoking

People with schizophrenia have consistently been shown to have very high rates of cigarette smoking. Up to 88 percent of all patients smoke, as compared to 25 per cent of the general population. Some studies have linked this high rate to the clinical characteristics of schizophrenia, suggesting that the gene for the alpha 7-nicotinic receptor may play a role in the pathogenesis of the illness and may also be responsible for the heavy smoking among patients. However, as this high smoking rate represents a significant health and financial cost to patients, other studies are exploring ways to help them quit.

Supported by SRI, one such study* conducted at the Centre for Mental Health Studies (CMHS), University of Newcastle, recruited 298 regular smokers with a psychotic disorder. Half the group participated in a 12-month intervention therapy program, and the other half in their usual care control program. The intervention program consisted of nicotine replacement therapy, plus motivational interviewing and cognitive-behaviour therapy (MI/CBT). The results showed that those patients who completed all sessions of the intervention program were 20 percent more likely to achieve abstinence or significant smoking reduction.

Quitting Street Drugs

Another study** conducted at CMHS investigated whether an intervention program of motivational interviewing and cognitive-behaviour therapy was more effective than routine treatment in reducing cannabis, alcohol and/or amphetamine use. Similar to the smoking study, 160 substance using schizophrenia patients were divided into two groups, one of which received the 10-session MI/CBT intervention program.

While some temporary benefits were noted during participation in the program, there were no differences in terms of frequency of drug use between the treated and untreated groups 12 months after the treatment. These results indicate that MI/CBT alone is ineffective in aiding schizophrenia patients to break addiction to street drugs.

A FAT Chance of Becoming Manic-Depressive First bipolar disorder risk gene found

SRI’s Dr Albert Chetcuti has collaborated on a study led by scientists at the Garvan Institute of Medical Research and the University of New South Wales, which has discovered the first risk gene specifically for bipolar disorder, also known as manic-depressive illness. The discovery has shown that people who have a particular form of this gene are twice as likely to develop the disease.

Dr Ian Blair, lead investigator of the study*, says: “We are the first group in the world to take a multi-faceted approach to identify a bipolar risk gene – we used a number of families, unrelated patients, and therapeutic drug mouse models. Each of these three lines of investigation led us to a gene called FAT.”

“We know that the FAT gene codes for a protein that is involved in connecting brain cells together, what we need to do now is find out exactly how it contributes to the increased risk of bipolar disorder,” explained Dr Blair.

Bipolar disorder is a major psychiatric illness affecting around one person in every 50. Tragically, around one in six people suffering from the condition will suicide. Mood-stabilising medications are typically prescribed to help control bipolar disorder. Lithium was the first mood- stabilising medication approved by the U.S. Food and Drug Administration (FDA) for treatment of mania. For decades it has been widely prescribed for treatment of bipolar disorder, yet no one knows for sure why it works.

Dr Blair’s research has raised the possibility that lithium exerts its therapeutic affect by altering FAT gene expression, as well as the expression of genes encoding FAT’s protein partners.

Lithium has a number of severe side effects that include tremor and weight gain. Kidney dysfunction may develop in a small proportion of patients when it is administered for long periods of time.

“Once we understand exactly what the FAT gene does, we will be able to develop better diagnostic tests for bipolar disorder. In the future, we hope our research will lead to new, targeted medicines specifically for bipolar disorder that don’t have the unpleasant side effects that lithium has”, said Dr Blair.